引言
肿瘤细胞的快速增殖和持续分裂依赖膜脂的加倍。因此旺盛的脂质合成被认为是肿瘤细胞代谢的关键特征之一【1-3】。ATP-柠檬酸裂解酶（ATP-citrate lyase, ACLY）是脂肪酸合成代谢途径的第一个关键酶，催化底物柠檬酸与CoA形成脂肪酸从头合成所需的二碳单位乙酰辅酶A。ACLY的表达和活性受到磷酸化、乙酰化和泛素化的调节【4-7】，而近期研究发现，ACLY也可以发生O-GlcNAc糖基化修饰。O-GlcNAc糖基化修饰被广泛认为是一种可以感受营养波动的“sensor”【8-12】，但ACLY的O-GlcNAc糖基化修饰如何感知营养丰度及其生物学意义亟待揭示。
2024年10月10日，东北师范大学分子表观遗传学教育部重点实验室魏民、冯云鹏研究团队在PNAS上发表的题为O-GlcNAcylation of ATP-citrate lyase couples glucose supply to lipogenesis for rapid tumor cell proliferation的研究论文，报道了O-GlcNAc糖基化修饰在ACLY活性调节中的关键作用。
模式图（Credit: PNAS）
值得注意的是，已知生长因子EGF可以通过提高ACLY S455的磷酸化修饰，增强底物柠檬酸与ACLY的结合，提高ACLY的酶活性【6,13-17】。而该研究阐释的是ACLY S979的O-GlcNAc糖基化修饰增强另一底物底物CoA与ACLY的结合，且这两个位点的修饰对于产物的生成缺一不可。尽管ACLY S455的磷酸化与S979的糖基化两种修饰之间并不存在“cross-talk”，但EGF信号通过促进葡萄糖的吸收，进而上调ACLY的O-GlcNAc糖基化修饰。显然，决定ACLY活性的营养依赖的糖基化修饰和丝裂原信号指导的磷酸化修饰直接或间接地受EGF信号调控。该研究一方面阐释了细胞如何感知糖类物质的丰度指导脂肪酸合成进而促进细胞增殖的机制；另一方面也为从演化视角思考多细胞复杂有机体的细胞增殖调控机制增添了新的理解：虽然多细胞复杂有机体的增殖受丝裂原信号的控制，但决定单细胞生物增殖的古老的营养感知机制是保守的，丝裂原信号促进细胞增殖的过程依然需要通过特定的营养“检查点”（checkpoint）的核验。参考文献
1. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016. 16(11): 732-749.2. Snaebjornsson MT, Janaki-Raman S, Schulze A. Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer. Cell Metab. 2020. 31(1): 62-76.3. Storck EM, Özbalci C, Eggert US. Lipid Cell Biology: A Focus on Lipids in Cell Division. Annu Rev Biochem. 2018. 87: 839-869.4. Lin R, Tao R, Gao X, et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell. 2013. 51(4): 506-518.5. Zhang C, Liu J, Huang G, et al. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev. 2016. 30(17): 1956-70.6. Lee, JV, et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab 2014;20:306-319.7. Icard P, Wu Z, Fournel L, Coquerel A, Lincet H, Alifano M. ATP citrate lyase: A central metabolic enzyme in cancer. Cancer Lett. 2020. 471: 125-134.8. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005. 24(41): 6314-22.9. Qin W, Lv P, Fan X, et al. Quantitative time-resolved chemoproteomics reveals that stable O-GlcNAc regulates box C/D snoRNP biogenesis. Proc Natl Acad Sci U S A. 2017. 114(33): E6749-E6758.10. Wang Y, Liu J, Jin X, et al. O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect. Proc Natl Acad Sci U S A. 2017. 114(52): 13732-13737.11. Rao X, Duan X, Mao W, et al. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth. Nat Commun. 2015. 6: 8468.12. Yi W, Clark PM, Mason DE, et al. Phosphofructokinase 1 glycosylation regulates cell growth and metabolism. Science. 2012. 337(6097): 975-80.13. Guo, D, et al. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci Signal 2009;2:ra82.14. Tomas, A, Futter, CE, Eden, ER. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol 2014;24:26-34.15. Manning, BD, Toker, A. AKT/PKB Signaling: Navigating the Network. Cell 2017;169:381-405.16. Potapova, IA, El-Maghrabi, MR, Doronin, SV, Benjamin, WB. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 2000;39:1169-1179.17. Kanao, T, Fukui, T, Atomi, H, Imanaka, T. Kinetic and biochemical analyses on the reaction mechanism of a bacterial ATP-citrate lyase. Eur J Biochem 2002;269:3409-3416.https://doi.org/10.1073/pnas.2402674121责编|探索君
排版|探索君
文章来源|“BioArt”
End
